Project Summary Acute cough or lower respiratory tract infection (LRTI) is responsible for 27 million ambulatory visits per year, 70 million lost days of work and an economic impact of $40 billion annually. Antibiotics are widely used, despite guidelines recommending against their routine use, contributing to increasing rates of antibiotic resistance. This will be the first large observational study in the US primary care setting to gather data regarding clinical presentation, evaluation, management, and outcomes for 1400 patients with LRTI. Specific aims are: Aim 1: To describe the causes of LRTI and develop an evidence-base regarding geographic, seasonal and annual variation in primary and urgent care settings. We will compare our clinic-based results with those of the CDC?s laboratory-based surveillance systems for key pathogens. Aim 2: To use data from the first 933 patients recruited to develop and validate a clinical decision rule (CDR) that use surveillance data, signs, symptoms, and c-reactive protein (an inflammatory biomarker) to identify patients with a high (> 97%) likelihood of having a self-limited, uncomplicated course. We will then prospectively validate the CDRs using the final 467 patients recruited. Aim 3: To externally validate clinical decision rules previously developed by others for the diagnosis of influenza, the diagnosis of pertussis, and to rule out complicated or prolonged course of LRTI. Aim 4: To describe the natural history of each pathogen and for common clinical syndromes, to describe the impact on healthcare utilization and work loss, and to use propensity score matching to explore the efficacy of treatments for LRTI to be tested in subsequent clinical trials. To address these aims, we will recruit a diverse sample of 1400 outpatients presenting with LRTI to one of 6 ambulatory sites in 3 US states over 4 years. For each patient, we will gather demographics, desire for antibiotics, signs, symptoms, CRP, and a respiratory PCR panel for 22 viral and bacterial pathogens, as well as 4 weeks of follow-up regarding symptoms, complications, and healthcare utilization. We will use standard (regression, CART) and exploratory (LASSO, neural nets) methods to develop and validate novel CDRs to help physicians better target antibiotic use by identifying patients likely to have an uncomplicated course. We will also prospectively evaluate the accuracy, discrimination, and calibration of 7 previously developed CDRs. Key innovations include: 1) first large observational study of LRTI in US to link signs, symptoms, and clinical follow-up to a state of the art 22 pathogen respiratory panel, 2) largest ambulatory study to gather primary data regarding healthcare utilization, treatment patterns, and natural history of specific pathogens and clinical syndromes in primary care, 3) largest to develop and validate important CDRs that will help target antibiotic prescribing, and 4) will provide guidance for how to use new PCR technologies as they migrate to ambulatory and primary care settings. The tools and strategies developed will be evaluated in subsequent clinical trials for their ability to enhance antibiotic stewardship in the outpatient setting and reduce inappropriate prescribing, and for their impact on patient satisfaction and clinical outcomes.